The TGF-beta superfamily includes the bone morphogenic proteins (BMP), which were initially isolated from bone and defined by their ability to induce bone formation when implanted subcutaneously. The expression of BMPs in tissues other than bone, and in particular the abundant expression of BMP-3, BMP-4, and BMP-7 (osteogenic protein-1, OP-1) in kidney, suggest that they may have other important actions. In the developing kidney, OP-1 is produced by the advancing ureteric bud and by mesenchymal cell condensates. We have examined the role of OP-1 in organ culture of mouse metanephric rudiments from embryonic day 11.5 (prior to penetration by ureteric bud and therefore composed of uninduccd mesenchyme) and embryonic day 12.5 (after penetration by ureteric bud and therefore showing mesenchymal transition to epithelial tissue). We have found that 1) the addition of recombinant soluble OP-1 to day 11.5 metanephroi induces undifferentiated mesenchyme to undergo conversion to epithelium and 2) the addition of either neutralizing antibody or antisense to OP-1 to day 12 metanephroi antagonizes epithelial differentiation. These findings support a role for OP-1 in inducing the mesenchymal to epithelial transformation, and further suggest that OP-1 may play a critical, previously unrecognized role in renal development. Local, intra-renal TGF-beta 1 production is a well-recognized mediator in experimental animal models of chronic renal disease. We have identified and characterized a renal syndrome caused by elevated plasma levels of TGF-beta 1, using a mouse transgenic for TGF-beta l under the control of the albumin promoter, in which transgene expression is confined to the liver. These mice have plasma TGF-beta 1 levels which are 8-fold elevated at 3 weeks of age. Renal disease is notable for activation of the glomerular endothelial cell and expansion of the mesangium, present by 3 weeks of age. There is accumulation of extracellular matrix within the glomerulus and interstitium, including collagens I and III. Northern analysis indicates that this accumulation is due to a combination of increased rnRNA for collagen I and III and the proteoglycans biglycan and decorin and a striking increase in TIMP-1 mRNA. These findings suggest that circulating levels of TGF-beta can induce severe renal disease, at least in part by altering matrix remodelling within the kidney. We are testing the ability of TGF-beta 1 antagonists to retard renal disease in this model, including neutralizing antibody.